Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies

Shen, Chen‐Hsiang; Lin, Ying‐Cing; Xu, Kai; Nair, Usha; Pereira, Lais; Tripathi, Prabhanshu; Arnold, Johan; Chuang, Gwo-Yu; Melzi, Eleonora; Schön, Arne; Zhang, Baoshan; Dillon, Marlon; Bonilla, Brian; Flynn, Barbara J.; Kirsch, Kathrin H.; Kisalu, Neville K.; Kiyuka, Patience K.; Liu, Tracy; Ou, Li; Pancera, Marie; Rawi, Reda; Reveiz, Mateo; Seignon, Kareen; Wang, Lawrence T.; Waring, Michael T.; Warner, John E.; Yang, Yongping; Francica, Joseph R.; Idris, Azza H.; Seder, Robert A.; Kwong, Peter D.; Batista, Facundo D.

doi:10.1016/j.immuni.2021.10.017

Cited by 25 publications

(33 citation statements)

References 59 publications

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“…The 35 in silico designed antibody variants were produced and antigenically assessed using AlphaLISA, which provided an apparent affinity based on chemiluminescent signals. First, the supernatants of the antibodies were expressed and assessed for their reactivity to the junctional peptide NPDP19, as the affinity to NPDP19 has been shown to have high correlation with function and malaria protection efficacy (Kratochvil et al, 2021). From the initial 35 in silico designs, 27 successfully expressed ( Table 2 ) and 11 showed improved binding when compared to m43.151 ( Figure S2A ).…”

Section: Resultsmentioning

confidence: 99%

“…Overall, predictions suggest position 100 in the heavy chain to be important as it was frequently mutated. Most of the mutations identified by the in silico pipeline had not been elicited in previous murine models from which the template antibodies where derived (days 13 and 28 from immunization), with the exception of T96M H ( Figure S1B ) (Kratochvil et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

“…The Fc-modified variant, CIS43LS showed promising results in phase I human clinical trials, with a single administration protecting against malaria infection for over 9 months (Gaudinski et al, 2021; Kisalu et al, 2021). More recently (Kratochvil et al, 2021), two variants m42.127 and m43.151 were elicited from a CIS43-germline knock-in mice vaccinated with a KLH-based prototype malaria vaccine candidate. These antibodies were used to design the best-in-class antibody, iGL-CIS43.D3, which was ∼10 fold better than wild-type CIS43 (Kratochvil et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Antibody improvement can be performed through multiple methods, both experimental and computational, with increasing computational speeds highlighting the potential of in silico approaches. While direct in silico simulations of liver burden protection are not yet feasible, it is possible to use interaction energies between in silico mutated antibody variants and junctional peptide 21 as a surrogate for binding affinity, which has been shown to correlate with improved liver burden protection (Kratochvil et al, 2021). Because of the large number of potential antibody mutations to be screened, we developed a method that could be scaled for thousands of mutants, through mutating residues and short energy minimizations followed by a single molecular dynamics step to define interface and stability interaction energies.…”

Section: Introductionmentioning

confidence: 99%

“…More recently (Kratochvil et al, 2021), two variants m42.127 and m43.151 were elicited from a CIS43-germline knock-in mice vaccinated with a KLH-based prototype malaria vaccine candidate. These antibodies were used to design the best-in-class antibody, iGL-CIS43.D3, which was ~10 fold better than wild-type CIS43 (Kratochvil et al, 2021). These results highlight the potential of CIS43 variants in the fight against malaria.…”

Section: Introductionmentioning

confidence: 99%

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In Silico Improvement of Highly Protective Anti-Malarial Antibodies

Mateo

Tripathi

Pereira

et al. 2022

Preprint

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Antibody CIS43 binds Plasmodium falciparum circumsporozoite protein (PfCSP) and protects against malaria, as recently demonstrated clinically. To improve the efficacy of CIS43, we developed an in silico pipeline to optimize the interaction energy of CIS43 to its junctional epitope (peptide 21: PfCSP residues 101-115). Starting from two improved CIS43 variants, recently elicited from a CIS43-germline knock-in mice, single and double amino acid substitutions in the peptide 21-proximal heavy (VH) and light (VL) variable regions were introduced. CIS43-variants, selected on the basis of improved in silico interface and stability energies, showed increased affinity to peptide 21 and superior malaria-protective efficacy. The best designed variant, antibody P3-43, was significantly more protective than its template antibody m43.151, with greater liver-burden protection than the current best-in-class (antibody iGL-CIS43.D3). Crystal structures of improved antibodies revealed atomic-level interactions explaining gains in binding affinity. The reported pipeline provides a powerful in silico approach to improve antibody functionality.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In Silico Improvement of Highly Protective Anti-Malarial Antibodies

Mateo

Tripathi

Pereira

et al. 2022

Preprint

Self Cite

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Progress in building clinically relevant patient‐derived tumor xenograft models for cancer research

Wang,

Li,

Lin

et al. 2023

Anim Models and Exp Med

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Patient‐derived tumor xenograft (PDX) models, a method involving the surgical extraction of tumor tissues from cancer patients and subsequent transplantation into immunodeficient mice, have emerged as a pivotal approach in translational research, particularly in advancing precision medicine. As the first stage of PDX development, the patient‐derived orthotopic xenograft (PDOX) models implant tumor tissue in mice in the corresponding anatomical locations of the patient. The PDOX models have several advantages, including high fidelity to the original tumor, heightened drug sensitivity, and an elevated rate of successful transplantation. However, the PDOX models present significant challenges, requiring advanced surgical techniques and resource‐intensive imaging technologies, which limit its application. And then, the humanized mouse models, as well as the zebrafish models, were developed. Humanized mouse models contain a human immune environment resembling the tumor and immune system interplay. The humanized mouse models are a hot topic in PDX model research. Regarding zebrafish patient‐derived tumor xenografts (zPDX) and patient‐derived organoids (PDO) as promising models for studying cancer and drug discovery, zPDX models are used to transplant tumors into zebrafish as novel personalized medical animal models with the advantage of reducing patient waiting time. PDO models provide a cost‐effective approach for drug testing that replicates the in vivo environment and preserves important tumor‐related information for patients. The present review highlights the functional characteristics of each new phase of PDX and provides insights into the challenges and prospective developments in this rapidly evolving field.

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Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies

Cited by 25 publications

References 59 publications

In Silico Improvement of Highly Protective Anti-Malarial Antibodies

In Silico Improvement of Highly Protective Anti-Malarial Antibodies

Progress in building clinically relevant patient‐derived tumor xenograft models for cancer research

Improved HIV-1 neutralization breadth and potency of V2-apex antibodies by in silico design

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